The present invention relates to the discovery, identification, and characterization of novel human polynucleotides encoding proteins that share sequence similarity with animal phosphatases. The invention encompasses the described polynucleotides, host cell expression systems, the encoded proteins, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that either lack or over express the disclosed genes, antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed genes that can be used for diagnosis, drug screening, clinical trial monitoring, the treatment of physiological disorders, or otherwise contributing to the quality of life.
Membrane proteins can act as, inter alia, ligand receptors, signal transducers, neuronal guidance proteins, cell adhesion proteins, cell surface markers, and can also possess enzymatic functions such as the phosphorylation of substrates (i.e., kinase activity). Phosphatases mediate dephosphorylation of a wide variety of proteins and compounds in the cell. Often working in conjunction with kinases, phosphatases are involved in a regulating a wide range of biochemical and physiological pathways. Given the physiological importance of phosphatases, they have been subject to significant scrutiny and are good drug targets.
The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human proteins and the corresponding amino acid sequences of these proteins. The novel human proteins (NHPs) described for the first time herein share structural similarity with animal immunoglobulin super family cell surface proteins, proteins that play a role in neuronal guidance (e.g., nope, punc, unc, and neogenin), phosphatases, netrin receptors, DCC (deleted in colon cancer) including, but not limited to tyrosine phosphatases, and cell adhesion molecules as homologues and orthologs across a range of phyla and species.
The novel human polynucleotides described herein, encode open reading frames (ORFs) encoding proteins of 1,069, 380, 904, 1150, 985, 991, 302, 826, 1072, 907, 712, 624, 547, 793, and 628 amino acids in length (see SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30 respectively).
The invention also encompasses agonists and antagonists of the described NHPs, including small molecules, large molecules, mutant NHPS, or portions thereof that compete with native NHPs, NHP peptides, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NHPs (e.g., antisense and ribozyme molecules, and gene or regulatory sequence replacement constructs) or to enhance the expression of the described NHP polynucleotides (e.g., expression constructs that place the described gene under the control of a strong promoter system). The present invention also includes both transgenic animals that express a NHP transgene, and NHP xe2x80x9cknock-outsxe2x80x9d (which can be conditional) that do not express a functional NHP. Knockout murine ES cells have been produced in a murine ortholog of the described NHPs.
Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP product activity that utilize purified preparations of the described NHPs and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.
The Sequence Listing provides the sequence of the novel human ORFs encoding the described novel human phosphatase proteins. SEQ ID NO:31 describes a NHP ORF and flanking sequences.